Psoriasis is a common skin disease, occurring in approximately 2% of the population in Western countries. This skin disorder is characterized by erythema, indurations and scaling, and manifests most commonly as well-circumscribed, erythematous papules and plaques covered with scales.
Psoriasis is an autoimmune skin disease associated with a chronic inflammation. The presence of an unknown antigen causes the generation of effector T cells that infiltrate the skin and initiate a pathogenic process by producing different types of cytokines, including TNFα. Psoriatic lesions are also characterized by increased angiogenesis and vascular remodeling. Moreover, the increased proliferation and differentiation of keratinocytes may be responsible of the scaling aspects of psoriatic skin.
Therefore, the pathogenesis of psoriasis involves three different pathways: (1) angiogenesis, (2) inflammation and (3) keratinocytes hyperproliferation. In order to efficiently treat psoriasis, there is thus a need for a compound or a composition regulating these three pathways.
Insulin receptor substrate 1 (IRS-1) is a cytoplasmic docking protein involved in angiogenesis: it functions as an essential signaling intermediate downstream of activated cell surface receptors, including insulin, insulin-like growth factor 1 (IGF-1), prolactin, growth hormone (GH), vascular endothelial growth factor (VEGF) receptors, members of the integrin receptor family, and cytokine receptors. The inhibition of IRS-1 is thus a promising way to inhibit angiogenesis.
GS-101 (WHO INN Aganirsen), an insulin receptor substrate-1 (IRS-1) antisense oligonucleotide, was described in the European patent EP 1 409 672 as useful for inhibiting angiogenesis.
Surprisingly, the Inventors showed that GS-101 inhibits cutaneous angiogenesis, but also keratinocytes hyperproliferation and inflammation within psoriatic skin, positioning GS-101 as a promising candidate as anti-psoriatic agent.
As psoriasis is a skin disorder associated with erythematous plaques, the most adapted administration route for a pharmaceutical agent is topical application on the skin, i.e. transdermal application. However, skin penetration of macromolecules, such as, for example, antisense oligonucleotides, is poor, due to the barrier function of stratus corneus.
Surprisingly, the Inventors also showed that the transdermal application of GS-101 on psoriatic skin leads to a therapeutically effective amount of the antisense oligonucleotide within both epidermal and dermal cells.